Absorbable copolyesters of poly(ethoxyethylene diglycolate) and glycolide

ABSTRACT

A semi-crystalline, absorbable copolyester composition comprising the reaction product of a polycondensation polyester and at least one lactone, wherein the polycondensation polyester comprises the reaction product of diglycolic acid and/or a derivative thereof and diethylene glycol; and the copolyester comprises about 30 to 60% by weight of the polycondensation polyester based on the total weight of the copolyester. Also medical devices such as absorbable sutures comprising such copolyesters and absorbable microspheres comprising such copolyesters and methods of making of such absorbable microspheres.

CROSS-REFERENCE TO RELATED APPLICATION

This application is a Continuation-in-Part of application Ser. No.11/554,675 filed on Oct. 31, 2006.

FIELD OF THE INVENTION

The present invention relates to a composition comprising asemi-crystalline, absorbable copolyester comprising the reaction productof a polycondensation polyester and at least one lactone, morespecifically, a semi-crystalline absorbable copolyester comprising thereaction product of poly(ethoxyethylene diglycolate) and glycolide,where the copolyester comprises about 30 to 60% by weight of thepoly(ethoxyethylene diglycolate) based on the total weight of thecopolyester. In addition, the present invention relates to absorbablemedical devices (e.g., sutures, meshes and microspheres) comprising suchcopolyesters and particularly to a method of making absorbablemicrospheres.

BACKGROUND OF THE INVENTION

Mechanical properties of a medical device can be made to vary dependingon the end use application for the device. For example, it is oftendesirable for surgical sutures to exhibit mechanical strength, such asstraight tensile strength and knot tensile strength. One technique forproducing surgical sutures having these desired properties is to utilizepolymers having some degree of crystallinity. Specifically, thecrystalline or ordered structure of the polymer imparts strength to amedical device produced therefrom, including but not limited to asurgical suture, surgical mesh, surgical staple, hemostatic clip, andthe like.

In general, however, the greater the crystallinity of an absorbablepolymer, the slower the rate of the absorption will be. Therefore, inthose applications where an absorbable medical device is desired, thereis a need to balance the level of crystallinity of the polymer againstthe absorbability thereof. For example, there are certain applicationswhere there is a need for an absorbable medical device to absorbquickly, such as episiotomy and plastic surgical applications, wherefast absorption of the medical device is highly desirable to improvepatient comfort and to achieve aesthetic outcomes.

Several approaches to increase the absorption or hydrolysis rate ofabsorbable polymers are known. For example, one approach is to lower thecrystallinity of the polymer to enhance the absorption or hydrolysisrate thereof. This may be done by randomizing the chemical structure ofthe polymer using, for example, different lactones in thecopolymerization step to reduce the overall crystallinity of thepolymer. However, the use of lactones to disrupt crystallinity haslimited impact due to the considerably higher hydrophobicity of lactone,causing the resultant polymer and medical device to be more hydrophobic,and absorption or hydrolysis to occur more slowly. In addition, loweringthe level of crystallinity of the polymer may adversely affect thephysical properties of the medical device prepared therefrom.

A second approach to increase the absorption or hydrolysis rate ofsynthetic absorbable polymers is to add a non-absorbable hydrophilicmoiety, e.g. a polyether such as polyethylene glycol (PEG), to increasethe hydrophilicity of the absorbable polymer. However, such approachwill result in poor mechanical properties of the medical device (e.g.tensile strength and modules) due to the general chemical structure ofaliphatic polyethers, and the addition of PEG moieties will reduce theoverall crystallinity of the polymers.

A third approach is to use a pre-degraded synthetic absorbable polymer.For example, an absorbable polymer may be subjected to a hydration stepor gamma irradiated to initiate the hydrolysis of the absorbablepolymer, thereby resulting in a pre-degraded product. However, problemsarising with the use of a pre-degraded synthetic absorbable polymerinclude difficulty in controlling the quality and stability of thepre-degraded polymer. More specifically, it may be difficult to achievereproducible levels of pre-degradation in the final product.

In another example, it may be desirable for medical devices to be in theform of an injectable composition, i.e., as a filler for soft tissueaugmentation, or in combination with a drug, i.e., as a drug deliverycarrier. For example, if the injectable composition or drug deliverycarrier is comprised of microspheres, it is desirable for themicrospheres to exhibit certain properties, i.e., the ability to passthrough a small needle for injection subcutaneously or intradermally, ordelivery in the peritoneal or pelvic cavity, without aggregating oragglomerating under pressure, thereby avoiding clogging of a deliverydevice such as a needle; and the ability to retain their distinctspherical shape without aggregating or agglomerating (hereinafterreferred to as “dimensional stability”), upon manufacture, storage andphysical transport. Furthermore, in some situations it may be desirablefor these microspheres to retain their distinct spherical shape afterimplantation, to avoid agglomeration of the microspheres subcutaneouslyor intradermally, which would produce an unnatural appearance in theskin. Finally, if the microspheres are used as drug delivery carriers,it is desirable for the microsphere to attain homogeneous encapsulationof pharmaceutical substances, while having sustained and controlledrelease property.

U.S. Patent Publication 2006/0051398 assigned to Ethicon, Inc.,describes a copolyester comprising the reaction product of apolycondensation polyester and at least one lactone, wherein thepolycondensation polyester comprises the reaction product of diglycolicacid and/or a derivative thereof and ethylene glycol. The productdescribed in this reference is useful for adhesion prevention. Thecopolyester described in this reference is fully amorphous withrelatively low molecular weight.

U.S. Pat. No. 5,644,002 also assigned to Ethicon, Inc., describesabsorbable polymers and blends of polycondensation polyester andaliphatic polyesters based on lactone monomers, where thepolycondensation polyester is the reaction product of diglycolic acidand an alcohol selected from selected from the group consisting ofglycerol, pentaerythritol, trimethylolpropane, hydroxyl terminatedpoly(ethylene glycol)s, ethylene glycol, 1,2-propanediol,1,3-propanediol, 1,4-butylene glycol, dipropylene glycol,1,5-pentanediol, 1,6-hexanediol, 1,7-heptanediol, and 1,8-octanediol.The absorbable polymers described in this reference are branched orcrosslinked fully amorphous soft materials.

U.S. Pat. Nos. 4,048,256, 4,095,600 and 4,122,129, assigned to AmericanCyanamid Company, describe biocompatible and absorbable polycondensationpolyesters, which are the polycondensation product of diglycolic acidand glycols such as ethylene glycol, diethylene glycol, 1,2-propyleneglycol, 1,3-propylene glycol, and the like. Specifically, U.S. Pat. No.4,095,600 describes a transesterification reaction product of (a) about2 to 50% by weight of a polycondensation polyester made of diglycolicacid and an unhindered glycol and (b) polyglycolic acid (PGA) ofmolecular weight above 30,000 Daltons before reaction. Although it isbelieved that the transesterification reaction product described in thisreference exhibits crystallinity, the absorbability thereof is notexpected to be very good due to the high melting point of the PGAmoieties.

Therefore, there remains a need for a synthetic absorbable polymer thatwill achieve faster absorption or hydrolysis, while preservingmechanical strength that is required, for example, for surgical sutures,and that may be used to produce microspheres for use as an injectablecomposition or drug delivery carrier.

SUMMARY OF THE INVENTION

Described herein are a composition comprising a semi-crystalline,absorbable copolyester comprising the reaction product of apolycondensation polyester and at least one lactone, wherein thepolycondensation polyester comprises the reaction product of diglycolicacid and/or a derivative thereof and diethylene glycol; and thecopolyester comprises about 30 to 60% by weight of the polycondensationpolyester based on the total weight of the copolyester; absorbablemedical devices including without limitation sutures, meshes andmicrospheres comprising such copolyesters; and a method of making ofabsorbable microspheres.

DETAILED DESCRIPTION

The present invention relates to a composition comprising asemi-crystalline, absorbable copolyester of a polycondensation polyesterand at least one lactone, more specifically, a semi-crystallineabsorbable copolyester comprising the reaction product ofpoly(ethoxyethylene diglycolate) (PEEDG) and at least one lactone, wherethe copolyester comprises about 30 to 60% by weight, preferably about 30to 50% by weight, of the poly(ethoxyethylene diglycolate) based on thetotal weight of the copolyester.

In one embodiment of the present invention, the copolyester comprisesthe reaction product of a polycondensation polymer and at least onelactone, wherein the polycondensation polyester comprises the reactionproduct of diglycolic acid and/or a derivative thereof and diethyleneglycol.

In another embodiment, the polycondensation polyester comprises thereaction product of diglycolic acid and/or a derivative thereof, up toabout 25 mole percent of an aliphatic diacid based on the total moles ofacid, and diethylene glycol. Specifically, the aliphatic diacid may bean aliphatic alpha-omega dicarboxylic acid, including but not limited to3,6-dioxaoctanedioic acid, 3,6,9-trioxaundecanedioic acid, andcombinations thereof.

The polycondensation polyester may be synthesized by conventionaltechniques. For example, in a condensation polymerization, diglycolicacid and diethylene glycol may be polymerized in the presence of acatalyst at elevated temperatures and reduced pressures. A variety ofcatalysts may be used, but organometallic compounds have been found tobe useful. The catalyst for the polycondensation step of the synthesisis preferably tin based, e.g., stannous octoate. The most desirablecatalyst is dibutyltin oxide and is present in the diglycolicacid/diethylene glycol monomer mixture at a sufficiently effective molarratio of monomer to catalyst, e.g., ranging from about 5,000/1 to about100,000/1. For example, the ratio of 10,000/1 has been found to be quitesuitable. The reaction is typically carried out at a temperature rangefrom about 100° C. to about 220° C., preferably from about 140° C. toabout 180° C., under an inert atmosphere until esterification ofdiglycolic acid is complete. Preferably, 165° C. has been found to be adesirable reaction temperature when employing a vertically stirredreactor. It should be noted that the optimum reaction temperature may bereactor and catalyst level dependent but can be found by one having onlyordinary skill through the use of experiments. The first stage of thepolycondensation reaction (inert gas at atmospheric pressure) isfollowed by polymerization under reduced pressure until the desiredmolecular weight and viscosity are achieved.

In the case of medical devices that are required to exhibit mechanicalstrength, the weight average molecular weight of the polycondensationpolymer can range from about 20,000 to about 50,000 g/mol, preferablyfrom about 30,000 to about 50,000 g/mol, most preferably about 40,000g/mol. This corresponds to an inherent viscosity range from about 0.68to about 1.0 dL/g. When the molecular weight of the polycondensationpolymer is lower than about 20,000 g/mol, the molecular weight of thefinal copolyester is too low to achieve the desired mechanicalproperties, for example, for suture applications. Although molecularweight can be increased with increasing reaction time, it becomesincreasingly difficult to achieve very high molecular weight. We havefound, in general, that a molecular weight of the polycondensationpolymer greater than about 50,000 g/mol, is not necessary to achievedesirable properties. One could however envision that this value is notan absolute bar. One might for instance, increase the molecular weightof the polycondensation polymer, and lower the amount of the lactonemonomer used in the preparation of the final copolyester.

In the case of microspheres, the weight average molecular weight of thepolycondensation polymer can range from about 5,000 to about 15,000g/mol, preferably from about 8,000 to about 12,000 g/mol, mostpreferably about 10,000 g/mol. This corresponds to an inherent viscosityrange from about 0.30 to about 0.40 dL/g. When the molecular weight ofthe polycondensation polymer is lower than about 5,000 g/mol, themolecular weight of the final copolyester is too low to achieve thedesired mechanical properties. In general, a molecular weight of thepolycondensation polymer greater than about 15,000 g/mol is unnecessaryto achieve desirable properties. One could however envision that thisvalue is not an absolute bar. One might for instance, increase themolecular weight of the polycondensation polymer, and lower the amountof the lactone monomer used in the preparation of the final copolyester.

PEEDG is a fully amorphous polycondensation product of diglycolic acidand diethylene glycol. When the diethylene glycol is used in excess, theresultant polycondensation product contains hydroxyl-capped end groups,and is then capable of serving as a macroinitiator in the subsequent,second stage ring-opening polymerization with a lactone monomer, such asglycolide. When PEEDG is reacted with lactone monomers such as glycolideand transesterification reactions are minimized, block glycolidesequences form and the resultant copolyester is a crystallizablematerial. More specifically, this results in a semi-crystallinecopolyester, having properties that are particularly advantageous forexample in fiber manufacturing processes. Additionally, thecrystallization rate of the copolyester is observed to be fast, which isanother advantageous property, for example, in fiber manufacturingprocesses. Finally, both the PEEDG and the copolyester product derivedtherefrom are hydrophilic and fast-absorbing polymers.

The amount of polycondensation polyester used to prepare the copolyesterof the present invention ranges from about 30 to 60% by weight,preferably about 30 to 50% by weight based on the total weight of thecopolyester.

Suitable lactone monomers that may be reacted with the polycondensationpolyester include, but are not limited to, glycolide, lactide (I, d, dl,meso), p-dioxanone, trimethylene carbonate, epsilon-caprolactone,delta-valerolactone, beta-butyrolactone, epsilon-decalactone,2,5-diketomorpholine, pivalolactone, alpha,alpha-diethylpropiolactone,ethylene carbonate, ethylene oxalate, 3-methyl-1,4-dioxane-2,5-dione,3,3-diethyl-1,4-dioxan-2,5-dione, gamma-butyrolactone,1,4-dioxepan-2-one, 1,5-dioxepan-2-one, 1,4-dioxan-2-one,6,8-dioxabicycloctane-7-one, and combinations of two or more thereof.The preferred lactone monomer includes glycolide.

In one embodiment, the copolyester may comprise the reaction product ofa polycondensation polyester such as poly(ethoxyethylene diglycolate)and a lactone such as glycolide.

In another embodiment, the copolyester may comprise the reaction productof a polycondensation polyester and two or more lactones. For example,the copolyester may comprise the reaction product of thepolycondensation polyester, at least 75 mole percent glycolide based onthe total moles of lactone, and a second lactone monomer.

The copolyesters of the present invention may be convenientlysynthesized by reaction of a dihydroxy poly(alkylene diglycolate)homopolymer or copolymer with a lactone by conventional techniques usingconventional processes. For example, the polycondensation polyester isused as an α,ω-dihydroxy macroinitiator in a subsequent ring openingpolymerization (ROP) with a lactone or a lactone mixture. The lactonemonomers are copolymerized into the polycondensation polyester in thepresence of a conventional organometallic catalyst at elevatedtemperatures. The catalyst for the ROP may be already present asresidual catalyst in the polycondensation polyester or may be additionalcatalyst added in this second step of the synthesis. A suitable catalystadded at the time of the ROP can be an organometallic catalyst. Thering-opening organometallic catalyst is preferably tin based, e.g.,stannous octoate, and is present in a sufficiently effective amount inthe monomer mixture, preferably at a molar ratio of lactonemonomer-to-catalyst ranging from about 20,000/1 to infinity (i.e. noadditional catalyst used). Thus one might utilize a tin-IV compound suchas dibutyltin oxide at a diacid, for instance, diglycolicacid-to-catalyst ratio of about 10,000/1 to prepare the polycondensationpolyester and then add a tin-II compound such as stannous octoate at alactone-to-added-catalyst molar ratio of about 240,000/1 at the time ofthe ring opening polymerization. The copolyesters of the presentinvention may be synthesized alternately with no additional catalystbeing added at the time of the ROP as described in Example 2A.

In the case of medical devices that are required to exhibit mechanicalstrength, the ROP step can be immediately conducted in the same reactoras that used to synthesize the polycondensation polyester immediatelyafter the completion of the polycondensation step, if the reactor canprovide adequate heat transfer and agitation. The lactone or lactonemixture can be added as a solid, a slurry, or in molten form.Alternately, the ROP can be conducted in a separate reactor at a laterdate, or in the reactor used for the polycondensation polyester at alater date. If this is the case, the polycondensation polyester isdischarged from its reactor and is stored in an environment thatminimizes water pick up and hydrolysis. In the case of adding glycolidemonomer, the monomer can be added as a solid. The reactor is closed andthe pressure reduced. The reactor is usually held under vacuum for aprolonged period of time, for instance overnight, to allow drying.Nitrogen is then introduced into the reactor to bring the pressure toslightly greater than one atmosphere, and the purge cycle repeated for atotal of three times. The temperature of the reaction mass is brought upto 130° C. Once at this temperature, the agitator is activated. Thetemperature is then increased to 150° C. to complete the mixing. Thismixing step is essential to produce the copolyesters of the presentinvention as inadequate mixing tends to allow the formation ofhomopolymeric sequences which can then crystallize to an extent greaterthan optimum. To ensure that reactants are fully mixed, in-situspectroscopic probes (such as Near-Infrared) can be conveniently used.If additional catalyst is to be added, it is typically added once thebatch has been completely mixed. The temperature is quickly brought upto the final reaction temperature, with 210° C. being a most preferredtemperature, and held there for typically 2 hours. The exact reactionconditions will depend on the catalyst and its level; final reactiontemperatures can vary from about 195° C. to 235° C., and more preferablyfrom about 200° C. to about 220° C. Reaction times can vary from about30 minutes to a few hours, depending on the catalyst and its level, andis typically conducted until the desired conversion of monomer topolymer is achieved.

In the case of microspheres, additional catalysts such as stannousoctoate, can be added in the ROP stage, while the temperature is quicklybrought up to the final reaction temperature, and held there fortypically 4-6 hours. The exact reaction conditions will depend on thecatalyst and its level; final reaction temperatures can vary from about210° C. to 240° C., and preferably from about 220° C. to 230° C.Reaction times can vary from about 4 hours to 6 hours, depending on thecatalyst and its level, and is typically conducted until the desiredconversion of monomer to polymer is achieved.

An alternate reaction scheme that has been employed to prepare thecopolyesters of the invention has involved adding the lactone as amolten stream into the reactor. Thus the polycondensation polyester isadded first, typically as a molten stream and the reactor evacuated. Thereactor is heated to 130° C. Molten glycolide (or other glycolide richmixture) at a temperature of about 100° C. is added to the reactor.Although the batch temperature drops slightly, it is quickly broughtback up to 130° C. at which point mixing is started. At this point, theprocess that was described above is followed.

In the case where it is desirable for the medical device to exhibittensile strength, the copolyesters of polycondensation polyester andlactones, will typically have a weight average molecular weight of about40,000 g/mol (a.k.a. Daltons) to about 100,000 g/mol, preferably about50,000 g/mol to about 80,000 g/mol, and more preferably about 60,000g/mol to about 80,000 g/mol. These molecular weights are sufficient toprovide an effective inherent viscosity, typically between about 1.0 toabout 2.5 deciliters per gram (dL/g), preferably about 1.2 to about 2.0dL/g, more preferably about 1.4 to about 1.8 dL/g, as measured in a 0.1g/dL solution of hexafluoroisopropanol (HFIP) at 25° C.

In the case of microspheres, the copolyesters of polycondensationpolyester and lactones, will typically have a weight average molecularweight of about 15,000 g/mol (a.k.a. Daltons) to about 30,000 g/mol,preferably about 18,000 g/mol to about 28,000 g/mol, and more preferablyabout 20,000 g/mol to about 26,000 g/mol. These molecular weights aresufficient to provide an effective inherent viscosity, typically betweenabout 0.4 to about 1.0 deciliters per gram (dL/g), preferably about 0.6to about 0.8 dL/g, more preferably about 0.6 to about 0.7 dL/g, asmeasured in a 0.1 g/dL solution of hexafluoroisopropanol (HFIP) at 25°C.

In the case where it is desirable for the medical device to exhibittensile strength, the crystallinity of the copolyester described hereinranges from about 10 to about 40% crystallinity, preferably from about20 to about 40%, and more preferably from about 20 to about 30%. In thecase of microspheres, the crystallinity of the copolyester describedherein ranges from about 10 to about 25% crystallinity, and preferablyfrom about 15 to about 20%. It has been discovered that the use ofdiethylene glycol to prepare the polycondensation product, PEEDG,instead of ethylene glycol as described in U.S. Patent Publication2006/0051398, results in a copolyester product that is semi-crystalline,instead of an amorphous product.

The copolyester having the weight average molecular weights describedherein may be extruded into fibers or sutures for use in a surgicalwound site or trauma site, or used to make other medical devices such asmeshes, or used to prepare microspheres. Alternatively, articles may bemolded from the copolyester described herein by various conventionalinjection and extrusion molding processes. For example, the copolyestermay be molded to form, without limitation, sutures, meshes, films,orthopedic devices and injection molded devices. Alternatively, thecopolyester may be a component of a medical device, i.e., thecopolyester may form one layer of a multi-laminate hernia repair mesh,or may be suspended in a polymer solution and coated onto at least aportion of a medical device.

Generally, the microspheres described herein may be made bycoacervation, solvent evaporation, and droplet extrusion with a spinningdisk. Other methods of manufacture that may be utilized for formation ofmicrospheres include but are not limited to spray coating, pan-coating,spray-drying, phase separation, emulsion polymerization, and interfacialpolymerization.

Preferably, the method for making microspheres includes dissolving thecopolyester described herein, having a crystallinity ranging from about10 to 25% and a molecular weight ranging from about 15,000 to 30,000g/mol, in a polar organic solvent to form a first solution phase,wherein the weight ratio of copolyester to the polar organic solvent mayrange from about 0.001 to about 1, and preferably from about 0.02 toabout 0.33. Then the first solution phase may be heated to about 50° C.to about 100° C., and the preheated first solution phase may besubsequently mixed with a volatile non-polar co-solvent to form an oilphase, wherein the ratio of the volatile non-polar co-solvent to thepolar solvent ranges from about 0.50 to about 30, and preferably fromabout 5 to about 15. The polar organic solvent is preferably DMSO andthe volatile non-polar co-solvent is preferably methylene chloride. Theoil phase formed above may then be transferred into an aqueous phase ina dropwise manner to form an oil in water emulsion (referring herein toa mixture of two immiscible substances), wherein the ratio of theaqueous phase to the oil phase ranges from about 1 to about 100, andpreferably from 5 to about at least 15. Methods of forming the emulsioninclude, but are not limited to, vortexting, mixing and homogenizing.The volatile non-polar co-solvent may then be removed from the oil/wateremulsion by evaporation, followed by removal of the polar organicsolvent from the oil/water emulsion. Upon drying, uniform and finemicrospheres comprised of the copolyester may be formed. Themicrospheres described herein have a particle size ranging from about 20to about 200 microns, and preferably from about 40 to about 100 microns,and are capable of retaining their distinct spherical shape duringmanufacture, storage, and physical transportation.

Optionally, the microspheres described herein may have incorporatedthereon or therein a hydrophilic active agent such as tranilast and thehydrophilic analogs and derivatives thereof. Preferably, the hydrophilicactive agent is tranilast. Tranilast, also known asN-(3,4-dimethoxycinnamoyl) anthranlic acid, or analogs thereof, iseffective for treating inflammation, allergies and asthma, and reducingor preventing formation of adhesions between tissue surfaces in bodycavities following surgical procedures when administered directly to thetissue and body cavity in amounts and under conditions effective toinhibit the formation of post-operative adhesions, as described in USPatent Application Nos. US2005/0106229A1 and US2005/0106230A1 to Cooper.The active agent may be incorporated into the first solution phasedescribed above by dissolving the copolyester and the hydrophilic activeagent in a common polar organic solvent, wherein the weight ratio ofcopolyester to hydrophilic drug may range from about 0.25 to about 10and preferably from about 2 to about 5. The amount of active agent mayrange from about 0.5 to 50 wt. %, based on the total weight of solidmicrospheres.

While the following examples demonstrate certain embodiments of theinvention, they are not to be interpreted as limiting the scope of theinvention, but rather as contributing to a complete description of theinvention.

EXAMPLE 1 Synthesis of Hydroxy Terminated Poly(ethoxyethylenediglycolate) (PEEDG)

A dual-agitated reactor with intermeshing HELICONE patterned blades(D.I.T. 10 CV reactor) was employed. After charging the reactor with 7.0kg of diglycolic acid, 16.6 kg of diethylene glycol (DEG) and 1.3 gramsof dibutyltin oxide catalyst, the pressure was reduced to below 1 Torrand the vacuum preserved over night. The next day vacuum was released byintroducing dry nitrogen (argon can be substituted) and heating of themixture was started, and the agitator was started and set to 15 RPM inreverse. When the reactor temperature reached 150° C., the agitatorspeed was reset to 20 RPM in a forward direction. Soon first distillateappeared containing mostly water, an esterification by-product. Thereaction was continued at 170° C. for about 2 hours until approximatelyall water was distilled and/or first traces of DEG appeared in thedistillate. After the first nitrogen/argon stage was completed, pressurewas lowered gradually to full vacuum while the temperature of the batchwas maintained at 170° C. A vacuum of about 30-50 mTorr was maintainedthroughout the rest of the reaction, a total time of approximately 80hours. Melt and solution viscosities were regularly checked to ensurepolycondensation polyester of a desired molecular weight. Hydroxyend-capped polycondensation polyester was discharged after approximately66 hours (sample 1A) and 80 hours (1B) of reaction time, respectively,under vacuum. Both portions were a fully amorphous, colorless viscousliquid with a glass transition temperature of about −13.0 and −11.5° C.,respectively. Weight average molecular weight was about 21,000 and27,000 g/mol respectively; the resin sample under vacuum for 66 hours(V+66 h) exhibited an inherent viscosity (IV) of 0.69 dL/g, while thesample discharged at V+80 hours had IV of 0.84 dL/g, as determined inHFIP at 25° C. at a concentration of 0.1 g/dL.

EXAMPLE 2A Synthesis of Copolyester IA: The Copolymerization of anα,ω-Dihydroxy Poly(ethoxyethylene diglycolate) Homopolymer with aLactone Monomer, Glycolide, (PEEDG/Gly 40/60)

A portion of the polycondensation polyester (7.4 kg) produced in Example1 (V+80, sample portion “B”) was held in the DIT 10 CV reactor at roomtemperature under nitrogen. A S/S melt-tank was used to melt thecrystalline glycolide, prior to the addition into the reactor with thepolycondensation polyester. The glycolide (11.1 kg) was charged to themelt-tank, pulled under vacuum, and then heated and held under nitrogenat 120° C. After the polycondensation polyester was heated toapproximately 120° C., at which point the molten glycolide monomer wastransferred from the melt tank with agitation. Agitator mixing wascontinued (20 RPM) and the batch temperature raised to 225° C. for ashort period, to assure that there was no PGA “freeze-up”. In situ, areal-time Fourier Transform Near-Infrared probe was used to confirmcomplete mixing of components. The temperature was then reduced to 210°C. and the reaction was continued for another two hours. The dischargedcopolyester was slightly crystalline, with a brownish to slightly yellowtint, and had a glass transition temperature of 14.5° C. Weight averagemolecular weight was approximately 60,000 g/mol and an inherentviscosity of 1.38 dL/g, as determined in HFIP at 25° C. at aconcentration of 0.1 g/dL, was recorded. The composition was confirmedby H¹NMR to be 40/60 by weight poly(ethoxyethylenediglycolate-co-glycolide).

The copolymer was sized to approximately 3/16″ granules in a rotatingknife granulator, sieved to remove fines, and placed in aPatterson-Kelley twin-shell tumble dryer. The resin was subjected tofull vacuum at ambient temperature for approx. 18 hours, at which pointheat was introduced to the dryer. The dryer was heated to 110° C. forapprx. 24 hours with full vacuum (<200 mtorr) at which point the heatwas removed, and the vessel allowed to cool to room temperature. Theresin was removed from the dryer, placed in vacuum containers and heldunder vacuum until further use.

The combined sources of tin in Example 2A result in alactone-to-total-tin-catalyst ratio of about 28,300/1. The total tin inthe final copolyester is about 32 ppm on a weight basis.

EXAMPLE 2B Synthesis of Copolyester IB: The Copolymerization of anα,ω-Dihydroxy Poly(ethoxyethylene diglycolate) Homopolymer with aLactone Monomer, Glycolide, (PEEDG/Gly 45/55)

A portion of a polycondensation polyester produced in a similar manneras described in Example 1 (8,3 kg) having weight average molecularweight of 42,500 g/mol and inherent viscosity of 1.16 dL/g, was reactedwith glycolide monomer (10.1 kg) by ring-opening polymerizationaccording to procedures described in Example 2A. Final compositionrevealed by NMR was PEEDG/Gly 45/55 wt. %. This copolymer issemi-crystalline, with the weight average molecular weight of 75,000g/mol and inherent viscosity of 1.64 dL/g.

EXAMPLE 2C Synthesis of Copolyester IC: The Copolymerization of anα,ω-Dihydroxy Poly(ethoxyethylene diglycolate) Homopolymer with aLactone Monomer, Glycolide, (PEEDG/Gly 50/50)

A portion of a polycondensation polyester produced in a similar manneras described in Example 1 (8,2 kg) having weight average molecularweight of 34,000 g/mol and inherent viscosity of 0.94 dL/g, was reactedwith glycolide monomer (8.2 kg) by ring-opening polymerization accordingto procedures described in Example 2A. Final composition revealed by NMRwas PEEDG/Gly 50/50 wt. %. This copolymer is semi-crystalline, with theweight average molecular weight of 55,000 g/mol and inherent viscosityof 1.35 dL/g.

EXAMPLE 3 Synthesis of Copolyester II: (PEEDG/Gly 30/70)

A portion of the polycondensation polyester produced as described inExample 1 (1.8 kg) having weight average molecular weight of 21,000g/mol and inherent viscosity of 0.69 dL/g (V+66 h, sample portion “A”),was reacted with glycolide monomer (4.2 kg) by ring-openingpolymerization according to procedures described in Example 2A. Finalcomposition revealed by NMR was PEEDG/Gly 30/70 wt. %. This copolymer issemi-crystalline, with the weight average molecular weight of 42,000g/mol and inherent viscosity of 1.18 dL/g.

EXAMPLE 4 Synthesis of Copolyester III (PEEDG/Gly 40/60)

A portion of the polycondensation polyester produced as described inExample 1 (6.1 kg) having weight average molecular weight of 12,700g/mol and inherent viscosity of 0.35 dL/g, was reacted with glycolidemonomer (9.1 kg) by ring-opening polymerization according to proceduresdescribed in Example 2A. The final composition revealed by NMR wasPEEDG/Gly 40/60 wt. %. This copolymer is semi-crystalline, with theweight average molecular weight of 24,000 g/mol and inherent viscosityof 0.80 dL/g.

EXAMPLE 5 Synthesis of Copolyester IV (PEEDG/Gly 30/70)

A portion of the polycondensation polyester produced as described inExample 1 (4.1 kg) having weight average molecular weight of 12,700g/mol and inherent viscosity of 0.35 dL/g, was reacted with glycolidemonomer (9.5 kg) by ring-opening polymerization according to proceduresdescribed in Example 2A. The final composition revealed by NMR wasPEEDG/Gly 30/70 wt. %. This copolymer is semi-crystalline, with theweight average molecular weight of 24,000 g/mol and inherent viscosityof 0.79 dL/g.

EXAMPLE 6

Melt index testings were conducted on several PEEDG/Gly copolymers todetermine their melt properties suitable for fiber extrusions. Meltindex testings are performed on Melt Index Plastometer (manufactured byTinius & Olsen, Willow Grove, Pa., USA). The procedure is described asfollows. The material to be tested is inserted into the bore of apreheated Plastometer (e.g. 195-235° C.) containing the designated die.A piston rod containing a known weight (e.g. 3,700 g) is placed on thetop of the polymer. The weight forces the melted polymer to flow througha die of predetermined length and diameter at the preset temperature(e.g. 195-235° C.), which is above the melting point of the polymer.Next, the portions of extruded polymers, obtained at designated timeintervals, are accurately weighed to determine a weight per unit of timemeasurements. Melt index (MI) is generally defined as grams of polymersthat are collected through the die for the time of 10 minutes. Usingthis method, accurate comparisons can be made to evaluate the flowcharacteristics of similar or different polymers at constant conditions.

TABLE 1 Melt index test of different PEEDG/Gly copolymers. Melt index,Copolyester Mw Tm MI ID Composition (g/mol) (° C.) Condition (g/10 min)Copolyester PEEDG/Gly 60,000 192 T = 235° C., 1.039 IA 40/60 w = 3,700 gT = 200° C., 0.372 w = 3,700 g Copolyester PEEDG/Gly 75,000 198 T = 235°C., 0.560 IB 45/55 w = 3,700 g T = 225° C., 0.417 w = 3,700 gCopolyester PEEDG/Gly 55,000 197 T = 225° C., 0.762 IC 50/50 w = 3,700 gCopolyester PEEDG/Gly 42,000 205 T = 235° C., Failed II 30/70 w = 3,700g T = 210° C., 1.075 w = 3,700 g T = 210° C., No flow w = 3,700 gCopolyester PEEDG/Gly 24,000 188 T = 225° C., Failed III 40/60 w = 3,700g T = 195° C., Failed w = 3,700 g Copolyester PEEDG/Gly 24,000 195 T =200° C., Failed IV 30/70 w = 3,700 g

“Failed” MI samples indicate that melt viscosity is too low for thesematerials to be measured. This indirectly implies that thesecopolyesters cannot be extruded into fibers. Data for Copolyester IIindicate that only extrusion at low temperature melt conditions(slightly above its melting point) may have suitable melt viscosity.

EXAMPLE 7

Crystallization properties of several PEEDG/Gly copolyesters weredetermined using differential scanning calorimetry (DSC). Overallcrystallization rates depend principally on two factors: theconcentration of growing spherulites over time (nucleation rate) and therate of spherulitic growth. As expected, these processes have ameasurable effect on calorimetric data. Calorimetric results weregenerated on a TA Instruments Differential Scanning Calorimeter, Model2910 MDSC, using dry N₂ as a purge gas. Crystallization studies wereconducted in the following manner: after melting, the sample wassubjected to the cooling step from the melt at a constant cooling rateof 10° C./min. Crystallization is manifested by the exothermic peak,whose high temperature slope is used to determine crystallization rate,while the area under the peak (heat of crystallization, ΔH_(C)) isassociated with the overall level of crystallinity.

TABLE 2 Crystallization properties of PEEDG/Gly copolyesters Cryst.Copolyester IV T_(cryst) ΔH_(c) Rate ID Composition (dL/g) (° C.) (J/g)(W/g/° C.) Copolyester PEEDG/Gly 1.38 137.0 39.5 −0.0342 IA 40/60Copolyester PEEDG/Gly 1.64 102.0 7.5 −0.0008 IB 45/55 CopolyesterPEEDG/Gly 1.35 95.0 2.0 −0.0003 IC 50/50 Copolyester PEEDG/Gly 1.18145.5 41.0 −0.0370 II 30/70 Copolyester PEEDG/Gly 0.80 119.5 42.5−0.0166 III 40/60 Copolyester PEEDG/Gly 0.79 101.5* 12.5 −0.0018 IV30/70 *another smaller crystallization peak observed at 205° C.

Data in Table 2 suggest that the copolyesters described herein cancrystallize under the specified cooling conditions from the melt (−10°C./min). Polymers with higher molecular weight and fastercrystallization kinetics may be easy to extrude into fibers. In the caseof copolyesters having low molecular weight and that crystallize slowly,such as copolyesters III and IV, it is not expected that these can beextruded into fibers. Therefore, for the copolyester to be extruded intofibers, first the copolyesters must have a suitable melt viscosity (MI)or sufficiently high molecular weight, and second, the copolyesters musthave relatively fast crystallization kinetics.

EXAMPLE 8 2/0 Monofilaments Produced from Copolyesters IA-C

Monofilaments 2/0 were made from Copolyesters IA-C as described aboveusing cold drawing procedure under following processing conditions:

Die temperature: 200° C. (Fiber-IA); 225° C. (Fiber-IB); 207° C.(Fiber-IC);

Water bath temperature: 20° C. (Fiber-IA); 40° C. (Fibers-IB&C);

Speed of the first set of Godets for all fibers (not heated): 15 RPM

Speed of the second set of Godets for all fibers (not heated): 100 RPM

Speed of the third set of Godets for all fibers (not heated): 110 RPM

Overall draw ratio for all fibers were 7.2

First oven temperature: 80° C. (Fiber-IA); 110° C. (Fiber-IB); 90° C.(Fiber-IC);

Second oven temperature: 95° C. (Fiber-IA); 110° C. (Fiber-IB); 100° C.(Fiber-IC);

Monofilaments appear to be smooth, pliable yet strong.

Selected thermal properties of the fibers are determined usingdifferential scanning calorimetry, and are listed in Table 3.

TABLE 3 Thermal and crystallization properties of the neat resin and ofthe selected experimental monofilaments Fiber Tensile Cryst. Strength TmΔHm Tc* ΔHc* Rate* Polymer (lbs) (° C.) (g/mol) (° C.) (g/mol) (W/g/°C.) Neat resin N/A 196.0 24.0 137.0 39.5 −0.034 IA Fiber-IA 13 193.522.0 132.0 37.5 −0.031 Neat resin N/A 198.0 25.0 102.0 7.5 −0.0008 IBFiber-IB 15 193.5 27.0 95.0 11.0 −0.0011 *data obtained from the coolingfrom the melt with the constant cooling rate of 10° C./min

DSC data indicate that the copolyesters (IA and IB) extruded under theconditions described above did not randomize appreciably compared to theoriginal copolyester (neat resin), and did not loose ability tocrystallize fast (compared to the neat resin), as indicated from thecrystallization rates in Table 3.

EXAMPLE 9

Tensile properties were determined using Instron testing machine on theunannealed monofilaments (Fiber-IA and Fiber-IC) and annealedmonofilament Fiber-IB (105° C. for 6 hours). Sample rate was 20 pts/secswith crosshead speed of 12 in/min; full scale load range=100 lbf. InTable 4, selected tensile properties (mean values) are given forFiber-IA, Fiber-IB, and Fiber-IC and for the same fibers with a singleknot made in the middle of the thread.

TABLE 4 Selected Tensile properties of unannealed Fiber-IA and Fiber-ICand annealed Fiber-1B Load at Stress at Young's Diameter the break maxload Elongation Modulus Sample (mil) (lbs) (kpsi) (%) (kpsi) Fiber-IA14.4 12.8 78.2 29.6 347 Fiber-IA 14.4 9.3 NA NA NA with a knot Fiber-IB12.9 15.0 112 56.0 164 Fiber-IB 12.9 9.7 NA NA NA with a knot Fiber-IC12.8 11.8 91.0 58.0  43 Fiber-IC 12.8 6.4 NA NA NA with a knot

As Table 4 indicates, excellent mechanical properties are observed forboth unannealed fibers (Fiber-IA and Fiber-IC), and annealed Fiber-IB.More significantly, substantial knot security was maintained (55 to 73%of the strength) for all samples as indicated in the Table 4.

EXAMPLE 10 Synthesis of Copolyester V: The Synthesis of an α,ω-DihydroxyPoly(ethoxyethylene diglycolate) Homopolymer with a Lactone Monomer,Glycolide, (PEEDG/Gly 40/60)

A portion of hydroxy end-capped polycondensation polyester, produced ina similar manner as described in Example 1, is used in this example. Thedischarge is a fully amorphous, colorless viscous liquid with a glasstransition temperature of about −15.0° C. Weight average molecularweight was about 14,000 g/mol (IV=0.35) respectively.

In the second stage, a portion of the polycondensation polyester (2.56kg) produced as above was held in the DIT 10 CV reactor at roomtemperature under nitrogen. A stainless steel melt-tank was used to meltthe crystalline glycolide, prior to the addition into the reactor withthe polycondensation polyester to be added later in a liquid state. Theglycolide (3.84 kg) was charged to the melt-tank, pulled under vacuum,and then heated and held under nitrogen at about 120° C. After thepolycondensation polyester was heated to approximately 120° C., thestannous octoate solution (0.417 ml in Toluene) was added in thereactor, and the molten glycolide monomer was transferred from the melttank with agitation. Agitator mixing was continued (20 RPM) and thebatch temperature raised to 240° C. for a short period, to assure thatthere was no PGA “freeze-up”. In situ, a real-time Fourier TransformNear-Infrared probe was used to confirm complete mixing of components.The temperature was then reduced to 220° C. and the reaction wascontinued for another four hours. The discharged copolyester wasslightly crystalline, with a brownish to slightly yellow tint, and had aglass transition temperature of 12.5° C. Weight average molecular weightwas approximately 24,000 g/mol and an inherent viscosity of 0.68 dL/g,as determined in HFIP at 25° C. at a concentration of 0.1 g/dL, wasrecorded. The material is semi-crystalline with the melting point ofabout 160° C. The overall crystallinity was about 20%. The compositionwas confirmed by H¹NMR to be 40/60 by weight poly(ethoxyethylenediglycolate-co-glycolide). The copolymer was sized and dried asdescribed in Example 2A.

EXAMPLE 11 Microsphere Preparation from Copolyester V

About 2 grams of the copolyester V described in Example 10 was dissolvedcompletely in about 8 grams of dimethyl sulfoxide, DMSO (Fluka, USA) atroom temperature using magnetic stirring to make a stock solution ofcopolyester and DMSO. Next, the specific amounts of co-solvent methylenechloride, CH₂Cl₂ (Aldrich, USA), shown in Table 5, were quicklytransferred by a syringe into 0.5 g of preheated (1 minute in oven at90° C.) stock solution that was previously supplemented with additionalamounts of DMSO (as shown in Table 5) and accompanied by vigorous mixing(i.e. shaking the whole mixture for 10 to 15 seconds) to reach thehomogenous state. While the solution of copolyester, DMSO and methylenechloride stayed perfectly clear, using a new 1 ml syringe, the wholeamount (1 ml) was slowly injected (drop-by-drop) into a 20 cc vialcontaining 10 grams of 3% wt. polyvinyl alcohol (PVA )/deionized watersolution (10/1 water/oil ratio). The PVA/water solution was continuouslymixed by a magnetic stir bar, producing a vortex at its surface. Theexact amounts of solvents used to add to 0.5 g of stock solution ofPEEDG/Gly 40/60 in DMSO are given in Table 5. The ratio of CH₂Cl₂/DMSOranged from 2.28 to 10.

TABLE 5 Time to Polymer CH₂Cl₂/ observe first Additional in DMSO sign ofDMSO DMSO CH₂Cl₂ Overall Wt. % cloudiness (grams) (wt. %) (g) ratioSolids (min) 0.0 20 0.91 2.28 7.08 0.4 0.5 10 2.05 2.28 3.28 1.2 1.0 73.19 2.28 2.13 2.1 1.5 5 4.32 2.28 1.58 2.8 2.0 4 5.47 2.28 1.25 2.0 2.53 6.61 2.28 1.04 4.8 0.0 20 2.00 5.0 4.17 0.2 0.5 10 4.50 5.0 1.85 1.11.0 7 7.00 5.0 1.19 2.0 1.5 5 9.50 5.0 0.88 3.5 2.0 4 12.0 5.0 0.69 3.72.5 3 14.5 5.0 0.57 2.0 0.0 20 4.00 10.0 2.27 1.5 0.5 10 9.00 10.0 1.011.8

After injection was completed, the copolyester, DMSO and methylenechloride in PVA/water phase emulsion was flushed by a dry nitrogen flowto encourage faster methylene chloride evaporation. Using a FT-NIR fiberoptic probe, it was determined that about 2 hours were needed for thecomplete removal of methylene chloride from the solution. The next stepconsisted of repetitively washing the solution with deionized water toremove DMSO. Initially, agitation was stopped to allow formedmicrospheres to precipitate at the bottom of a vessel. The water phaseabove is removed by a syringe, and replaced by deionized water. Aftercontinuous stirring for about 5-10 minutes, the process was repeatedthree times to ensure complete removal of DMSO. Finally, the formedmicrospheres were dried under vacuum at ambient temperature. As revealedby optical microscopy, the average diameter of these uniformlydistributed microspheres ranged from 20 to 80 microns, depending of thepercentage of solid (polymer) concentration in the oil phase. Higherpercentage of polymer in oil phase seems to produce smaller sizemicrospheres, and vise versa. Using this method, regular shapemicrospheres were formed in all solutions where the time withoutcloudiness exceeds 1 minute (the last column data in Table 5).

EXAMPLE 12 Microsphere Preparation from PEEDG/Gly 40/60 (Copolyester V)and Tranilast

About 2 grams of copolyester described in Example 10 was dissolvedcompletely in 8 grams of DMSO at room temperature under continuousstirring to make the same stock solution as described in Example 11.Tranilast (0.05 g) was mixed completely with 0.5 grams of PEEDG/Gly40/60 and DMSO stock solution. As a next step, 4 grams of methylenechloride was quickly transferred by a syringe into a preheated (1 minutein oven at 90° C.) solution of tranilast, copolyester and DMSOaccompanied by vigorous mixing, to form the oil phase. The overall ratioof CH₂Cl₂ to DMSO is 10. While the solution of tranilast, copolyester,DMSO and methylene chloride stayed perfectly clear, using a new 1 mlsyringe, the whole amount was slowly injected (drop-by-drop) into a 3%wt. of polyvinyl alcohol (PVA)/deionized water solution (10/1 water/oilratio). It is believed that up to 1/1 water/oil ratio can be used. ThePVA/water solution was continuously mixed by a magnetic stir bar. Afterinjection was completed, the tranilast, copolyester, DMSO and methylenechloride in PVA/water phase emulsion was flushed by a dry nitrogen flowto encourage faster methylene chloride evaporation to minimize the lossof tranilast into the water phase due to the solubility of the drug inthe hydrophilic solvent, DMSO. The next step consisted of repeatedlywashing the solution with deionized water to remove DMSO. Initially,agitation was stopped to allow the formed microspheres to precipitate atthe bottom of a vessel. The water phase above is removed by a syringe,and replaced by deionized water. After continuous stirring for about5-10 minute, the process was repeated three times to ensure removal ofDMSO from the microspheres. Finally, the formed polymer microspherescontaining tranilast were dried under vacuum at ambient temperature.Finally, uniformly distributed microspheres were formed with the averagediameter of 40-80 microns by this method, as confirmed by opticalmicroscopy.

EXAMPLE 13 Comparative (Use of DMSO only, Without the Combination ofCH₂Cl₂ and DMSO) Microsphere Preparation from Copolyester V

The procedure of making microspheres was the same as described inExample 11, except methylene chloride was not used as a cosolvent. Theclear solution of polymer in DMSO was slowly injected (drop-by-drop)using a 1 ml syringe into a 20 cc vial containing 10 grams of 3% wt.polyvinyl alcohol (PVA)/deionized water solution (10/1 water/oil ratio).No microspheres were formed by this method. Instead, nanoparticles ofpolymer dispersed into water/PVA were being detected.

EXAMPLE 14 Comparative (No Preheating of the Polymer/DMSO Solution Priorto the Addition of CH₂Cl₂) Microsphere Preparation from Copolyester V

If the stock solution of (2 g of Copolyester V/8 g of DMSO) is notheated before adding CH₂Cl₂, phase separation (cloudiness) occursquickly causing large agglomerates to appear instead of microspheres asdemonstrated herein. The procedure of making microspheres was similar tothat described in Example 11, except the polymer/DMSO solution was notpreheated prior to the addition of methylene chloride. The exact amountsof solvents used to add to 1.0 g of stock solution of Copolyester V inDMSO are given in Table 6

TABLE 6 Time to Additional CH₂Cl₂/ observe first DMSO CH₂Cl₂ DMSOPolymer/DMSO sign of (grams) (g) Overall ratio solution cloudiness 5.013.2 2.28 Cold Less than 10 sec 5.0 13.2 2.28 Hot More than 5 min

An addition of methylene chloride into cold polymer/DMSO solution causedthe fast precipitation (phase separation) of polymer causing solutioncloudiness to be observed before the oil phase could be injected intothe water/PVA solution. This consequently generates large particles tobe formed instead of microspheres. Also, further dilution of polymer inthe oil phase did not improve the solubility. On the other hand, whenthe polymer/DMSO solution was preheated according the proceduredescribed in Example 11, the oil phase stayed clear for a longer time,allowing the fine, uniform microspheres to be produced.

EXAMPLE 15 Comparative (Slow Transfer of Methylene Chloride intoPolymer/DMSO Solution) Microsphere Preparation from Copolyester V

The conditions are the same as in Example 14, except that methylenechloride wase added slowly in cold polymer/DMSO solution with mixing indiscrete steps until the overall ratio of CH₂Cl₂ to DMSO reach 2.28. Atthe end of this step, polymer precipitation from oil phase was even moreexcessive. Very non-homogeneous, gel-like structures were observedinstead of cloudy solutions. Similarly, when methylene chloride wereadded slowly to the same preheated polymer/DMSO solution in the samemanner as described above, similar non-homogeneous, gel-like structureswere observed instead of cloudy solutions.

EXAMPLE 16 Comparative (Fast Injection of the Oil Phase into Water/PVASolution) Microsphere Preparation from Copolyester V and Tranilast

Tranilast (12.5 mg) was mixed completely in 0.5 grams of CopolyesterV/DMSO stock solution as described in Example 12. Next, 4 grams ofmethylene chloride was quickly transferred by a syringe into thepreheated (1 minute in oven at 90° C.) solution of Tranilast, polymerand DMSO accompanied by vigorous mixing. The overall ratio of CH₂Cl₂ toDMSO was 10, and solution stayed for the time longer than 1 minute. Incontrast to the step described in the Example 3 where the oil phase wasinjected slowly (drop-by-drop) into the 3% wt. PVA/vortexed watersolution (10/1 water/oil ratio), this time the whole amount was injectedquickly in a couple of seconds. The result was generation of largeaggregates of polymer, and no microspheres were formed.

EXAMPLE 17 Comparative (Too Slow Agitation of Water/PVA Solution)Microsphere Preparation from Copolyester V and Tranilast

Tranilast (25 mg) was mixed completely in 0.5 grams of CopolyesterV/DMSO stock solution as described in Example 12. Next, 4 grams ofmethylene chloride was quickly transferred by a syringe into thepreheated (1 minute in oven at 90° C.) solution of Tranilast, polymerand DMSO accompanied by vigorous mixing. The overall ratio of CH₂Cl₂ toDMSO was 10, and solution stayed for the time longer than 1 minute, theoil phase was transferred drop-wise into the water phase. In contrast toExample 12, where vigorous mixing of 3% wt. PVA/water solution (10/1water/oil ratio) was accompanied by the appearance of vortex, this timethe agitation of water phase was slow and the vortex was hardly visible.The result was generation of a single large spherical ball of polymer,and no microspheres were detected.

EXAMPLE 18 Comparative

About 2 grams of Copolyester IB was added in 8 grams of DMSO at roomtemperature under continuous stirring and under these conditions thiscopolyester (Copolyester IB) could not go into the solution. Then themixture was heated at about 100° C. and only a small portion seemed tobe dissolved, but once the mixture was brought to an ambienttemperature, a gel structure (phase separation) quickly formed. The sameprocedure was repeated with a lower concentration of polymer (1 gram ofpolymer in 9 grams of DMSO) but the same phase separation occurred.

In a similar manner as described above, an attempt to dissolveCopolyester III in DMSO was made Copolyester III has comparablemolecular weight with the Copolyester V (about 25,000 g/mol), but theoverall crystallinity level of this material is relatively high (about32%). As was the case with Copolyester IB, Copolyester III showed a verylimited dissolution in DMSO with a gel like formation occurred rapidlyat ambient conditions.

This example demonstrates the effect of polymer molecular weight anddegree of crystallinity. Dissolution of higher molecular weight polymerand higher crystallinity polymer into DMSO, followed by treatment in asimilar manner as described above in Example 11, failed to yield fineand uniform micropspheres.

Although this invention has been shown and described with respect todetailed embodiments thereof, it will understood by those skilled in theart that various changes in form and detail thereof may be made withoutdeparting from the spirit and scope of the claimed invention.

1. A composition comprising an absorbable copolyester comprising thereaction product of a polycondensation polyester and at least onelactone monomer, wherein the polycondensation polyester comprises thereaction product of diglycolic acid and/or a derivative thereof anddiethylene glycol; the copolyester comprises about 30 to about 60% byweight of the polycondensation polyester based on the total weight ofthe copolyester; and the copolyester has a crystallinity ranging fromabout 10 to about 40%.
 2. The composition according to claim 1, whereinthe at least one lactone monomer is glycolide.
 3. The compositionaccording to claim 1, wherein the copolyester comprises the reactionproduct of a polycondensation polyester, at least 75 mole percentglycolide based on the total moles of lactone, and a lactone selectedfrom the group consisting of lactide (I, d, dl, meso), p-dioxanone,trimethylene carbonate, epsilon-caprolactone, delta-valerolactone,beta-butyrolactone, epsilon-decalactone, 2,5-diketomorpholine,pivalolactone, alpha,alpha-diethylpropiolactone, ethylene carbonate,ethylene oxalate, 3-methyl-1,4-dioxane-2,5-dione,3,3-diethyl-1,4-dioxan-2,5-dione, gamma-butyrolactone,1,4-dioxepan-2-one, 1,5-dioxepan-2-one, 1,4-dioxan-2-one,6,8-dioxabicycloctane-7-one, and combinations thereof.
 4. Thecomposition according to claim 1, wherein the polycondensation polyestercomprises the reaction product of diglycolic acid and/or a derivativethereof, up to about 25 mole percent of an aliphatic diacid based on thetotal moles of acid, and diethylene glycol.
 5. The composition accordingto claim 1, wherein the weight average molecular weight of thecopolyester is from about 40,000 to about 100,000 g/mol.
 6. Thecomposition according to claim 1, wherein weight average molecularweight of the copolyester is from about 50,000 to about 80,000 g/mol. 7.The composition according to claim 1, wherein weight average molecularweight of the copolyester is about 60,000 to about 80,000 g/mol.
 8. Thecomposition according to claim 1, wherein weight average molecularweight of the polycondensation polymer is from about 20,000 to about50,000 g/mol.
 9. The composition according to claim 1, wherein weightaverage molecular weight of the polycondensation polymer is from about30,000 to about 50,000 g/mol.
 10. The composition according to claim 1,wherein weight average molecular weight of the polycondensation polymeris about 40,000 g/mol.
 11. A surgical suture or mesh comprising anabsorbable copolyester that is the reaction product of apolycondensation polyester and at least one lactone monomer, wherein thepolycondensation polyester comprises the reaction product of diglycolicacid and/or a derivative thereof and diethylene glycol; the copolyestercomprises about 30 to about 60% by weight of the polycondensationpolyester based on the total weight of the copolyester; the copolyesterhas a crystallinity ranging from about 10 to about 40%; and the weightaverage molecular weight of the copolyester ranges from about 40,000 toabout 100,000 g/mol.
 12. The composition of claim 1, wherein thecopolyester has a crystallinity ranging from about 10 to 25% and saidcomposition is in the form of microspheres have a particular sizeranging from about 20 to about 200 microns.
 13. The compositionaccording to claim 12, wherein the copolyester has a crystallinityranging from about 15 to about 20%.
 14. The composition according toclaim 13, wherein the copolyester is the reaction product of thepolycondensation polyester and glycolide; and the polycondensationpolyester comprises the reaction product of diglycolic acid and/or aderivative thereof, and diethylene glycol.
 15. The composition accordingto claim 14, further comprising a hydrophilic active agent.
 16. Thecomposition according to claim 15, wherein the active agent is tranilastand the hydrophilic analogs and derivatives thereof.
 17. A method formaking microspheres comprising the steps of: (a) dissolving thecopolyester of claim 1 having a crystallinity ranging from about 10 to25% and a molecular weight ranging from about 15,000 to 30,000 g/mol;and/or hydrophilic drug in a common polar organic solvent to form afirst solution phase, wherein the weight ratio of copolyester to thepolar organic solvent ranges from about 0.001 to about 1; (b) heatingthe first solution phase at about 50 to about 100° C.; (c) mixing thepreheated first solution phase with a volatile non-polar co-solvent toform an oil phase, wherein the ratio of the volatile non-polarco-solvent to the polar solvent ranges from about 0.50 to about
 30. (d)transferring the oil phase into a vortexed aqueous phase in a dropwisemanner to form an oil in water emulsion, wherein the ratio of aqueousphase to the oil phase ranges from about 1 to about at least 100; (e)evaporating the volatile non-polar co-solvent from the oil/wateremulsion; (f) removing the polar organic solvent from the oil/wateremulsion thereby forming microspheres comprising the copolyester and/orhydrophilic drug; and (g) drying the microspheres.
 18. The methodaccording to claim 17, wherein the hydrophilic drug is tranilast; thepolar organic solvent is DMSO; the volatile non-polar co-solvent ismethylene chloride, and weight ratio of copolyester to hydrophilic drugranges from about 0.25 to about
 10. 19. The method according to claim17, wherein the weight ratio of copolyester to the polar organic solventranges from about 0.02 to about 0.33; the weight ratio of copolyester tohydrophilic drug ranges from about 2 to about 5;
 20. The methodaccording to claim 17, wherein the ratio of the volatile non-polarco-solvent to the polar solvent ranges from about 5 to about 15, whereinthe ratio of aqueous phase to the oil phase ranges from about 5 to aboutat least 15